Injectable composition with aromatase inhibitor

ABSTRACT

The present invention provides a composition suitable for forming an intramuscular implant. It comprises a biodegradable thermoplastic polymer of polylactic acid (PLA), DMSO and an aromatase inhibitor compound. The invention also provides a kit suitable for the in situ formation of the composition and its use as a medicine for treating cancer, especially breast cancer.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

The present application claims the benefit of and is a division of Ser.No. 14/610,362 filed Jan. 30, 2015, which is a continuation-in-part ofPCT/EP2013/065877, filed Jul. 29, 2013, which claims the benefit of ESP201231271 filed Aug. 2, 2012, and said application Ser. No. 14/610,362is also a continuation-in-part of and claims the benefit of Ser. No.14/555,273, filed Nov. 26, 2014, which is a continuation-in-part ofPCT/EP2013/061319, filed May 31, 2013, which claims the benefit of EP12170366.4, filed May 31, 2012, and said application Ser. No. 14/610,362is also a continuation-in-part of and claims the benefit of Ser. No.14/555,287, filed Nov. 26, 2014, which is a continuation-in-part of andclaims the benefit of PCT/EP2013/061320, filed May 31, 2013, whichclaims the benefit of EP 12170362.3, filed May 31, 2012, and saidapplication Ser. No. 14/610,362 is also a continuation-in-part of Ser.No. 13/690,647 filed Nov. 30, 2012, now U.S. Pat. No. 10,085,936 issuedOct. 2, 2018, which is a continuation-in-part of PCT/EP2011/059000,filed May 31, 2011, which claims the benefit of EP 10382154.2 filed May31, 2010, and said application Ser. No. 14/610,362 is also acontinuation-in-part of Ser. No. 13/690,707, filed Nov. 30, 2012, nowU.S. Pat. No. 10,058,504 issued Aug. 28, 2018, which is acontinuation-in-part of PCT/EP2011/059001, filed May 31, 2011, whichclaims the benefit of EP 10382153.4 filed May 31, 2010, the entiredisclosure of each of the above-cited patents and applications beinghereby incorporated herein by reference.

FIELD OF THE INVENTION

The present patent application is directed toward compositions useful incancer therapies.

In particular, the present invention refers to a composition suitablefor forming an intramuscular implant comprising a biodegradablethermoplastic polymer of polylactic acid (PLA), dimethyl sulphoxide(DMSO) and an aromatase inhibitor compound, a suitable kit for the insitu preparation of the composition and its use as a medicine for thetreatment of breast cancer.

BACKGROUND OF THE INVENTION

Without doubt, cancer treatments need to be developed, not only newmolecular entities but also pharmacological products for improvingpatients' quality of life. In this sense, the development of prolongedrelease formulations signifies an advance because they enable reducingthe total dose administered, increasing the duration of each dose andthe number of administrations and thereby creates a positive impact onthe emotional state of the patient.

The active ingredients (drugs) letrozole and anastrozole are the firstline active ingredients in the adjuvant treatment of postmenopausalwomen with hormone receptor-positive advanced breast cancer for whomthere is no alternative therapy beyond daily administration of a tablet.

Letrozole (4,4′-(1,2,4-triazol-1-ylmethyl)dibenzonitrile) andanastrozole(2,2′-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropanenitrile))belong to a class of drugs called non-steroidal inhibitors of aromataseand their mechanism of action consists of reducing the amount ofoestrogen in the body. This effect can decelerate or stop the growth ofmany types of cancer-producing cells in the breast that need oestrogento grow.

Currently, there is no formulation of letrozole on the market with theability to control the release of the drug over a long period of time.The pharmaceutical drug letrozole is currently only available in tabletform for daily oral administration. The formulations of letrozoledescribed here enable obtaining therapeutic levels of the drug in bloodfrom the start and continuously over a period of three months, avoidingthe need for daily dosing regimes and thereby improving the patient'squality of life.

In the treatment of breast cancer, as in the treatment of cancer ingeneral, the psychological state of the patient is very important;therefore the development of a three-monthly formulation of letrozoleand/or anastrozole means a substantial improvement in their quality oflife, reducing the impact that would result from daily treatment. Inturn, medical examinations that are carried out during monitoring of thedisease are normally conducted at 3 and 6 months over the first fewyears, so the administration of the formulation could coincide withconsultancy visits to the doctor.

Similar reasoning has led to the appearance on the market offormulations such as Zoladex®, a preformed implant of goserelin forsubcutaneous three-monthly application for the treatment of prostatecarcinoma, and Implanon®, a preformed implant of etonogestrel used as acontraceptive. However, these preformed implants show a series ofdisadvantages including:

-   -   The preparation of the implants by extrusion requires the use of        high temperatures, which can cause the degradation of the active        ingredient and the generation of potentially toxic impurities;    -   Low homogeneity of the product obtained when including active        ingredients at low doses;    -   Need for surgical procedures for implanting or injection of the        implant using large diameter needles.

It is also possible to find in the literature some publications onimplantable compositions of letrozole and/or anastrozole such as thefollowing.

For example, WO 2008/041245 describes implantable compositionscomprising a wide variety of active ingredients such as some aromataseinhibitors, including anastrozole, in a wide variety of administrationforms from preformed microparticles suspended in an aqueous vehicle toformulations that gellify in situ. Although it is doubtful that thisdocument can sufficiently support all the combinations of activeingredients and administration forms that may arise, the examples alwaysrefer to preformed microparticles, that is it never describes systems offorming implants directly “in situ”. Finally, it should be pointed outthat none of the examples show a duration of over 60 days.

WO 2010/065358 A1 describes compositions for the administration ofmedicines containing testosterone and an aromatase inhibitor forcontinuous administration of testosterone and for preventing itsconversion to estradiol. Although the description considers thepossibility that the form of administration may be an implant, the onlyexample of a form of administration is pellets.

WO 2012/074883 A1 describes biodegradable compositions foradministration of pharmaceutical drugs. These compositions require theuse of water-insoluble solvents such as benzyl benzoate or benzylalcohol in order to maintain the implant in a liquid or semi-solidstate. These solvents have been previously shown to provide suddenreleases and therefore are not suitable for the prolonged releasecompositions of the present invention.

US 2008/0206303 A1 describes prolonged release formulations ofanastrozole comprising a PLA or PLGA polymer that can be accompanied bya wide variety of solvents; however, in the embodiments of theinvention, the solvents used are benzyl alcohol andn-methyl-2-pyrrolidone (NMP), solvents that give rise to a very largeburst followed by a subsequent almost zero release. In fact, the burstthat was acceptable for the inventors in this document was 25-30% in oneday, a very high value, and because of this none of their exampleslasted more than 60 days; in particular in dogs, animals similar tohumans, release did not continue longer than 35 days. Finally, nomention was made in this document of letrozole particle size nor of theimportance of this factor in the behavior of the formulation.

Therefore, it would be desirable to obtain a three-monthly formulationof letrozole and/or anastrozole for first line adjuvant treatment ofbreast cancer in hormone receptor-positive postmenopausal women.

SUMMARY OF THE INVENTION

For this reason, the implants of the invention that are formed in situovercomes the majority of the drawbacks presented by currentformulations based on preformed implants. It offers an alternativepractical and effective therapy for the patient achieving therapeuticprofiles lasting for at least 60 days.

The term initial “burst” is understood as the ratio of the area underthe curve of plasma levels of the active ingredient (drug) in livinganimals obtained over the first 72 hours after intramuscularadministration of the product relative to the total area under the curve(also termed “AUC”) obtained at the end of a specified period, e.g. 30days, 60 days or 90 days, after the injection of an amount of letrozoleor anastrozole.

In order to obtain a prolonged release of active ingredient suitable forthe object of the present invention, the area under the curve of theburst is less than 10% compared to the total AUC, and ideally less than5%. Similarly, obtaining an equilibrium in the or a more level prolongedrelease profile of the aromatase inhibitor over at least 60 daysrequires that no more than 50% of the area under the curve of plasmalevels is obtained over the first 30 days after the injection. In otherwords, the preferred prolonged release of active ingredient is such thatthe area under the curve of the burst is less than 10% of the total AUCand not more than 50% of the total AUC is obtained over the first 30days after injection.

In some embodiments, the injectable depot composition provides a plasmalevel profile for drug as follows.

A first aspect of the invention provides a composition suitable forforming an intramuscular implant comprising a biodegradablethermoplastic polymer of polylactic acid (PLA), DMSO and an aromataseinhibitor compound of general formula (1):

wherein:

-   -   When R₁ is H; R₂ is

-   -   and R₃ is H    -   When R₁ is

-   -   R₂ is H and R₃ is CN characterized in that: a) the aromatase        inhibitor compound is in suspension in a solution containing        DMSO and PLA and represents between 15-50% by weight of the        total composition; b) the composition being able to solidify, to        form a solid or gel-type implant on contact with an aqueous        fluid or with the fluid of the body; and c) the composition        providing therapeutic plasma concentrations, after in vivo        administration, of at least 100 nmol/mL for not less than, for        at least or for more than 60 days following administration. The        plasma levels of letrozole should be sufficient to provide an in        vivo suppression of serum estrogens (E1 and E2) of at least        about 50% (E2, estradiol) and 70% (E1, estrone) and preferably        of at least about 60% (E1) and 80% (E2) in the steady state        during a dosing period. Some individual subjects may, on an        equivalent dose basis, exhibit plasma concentrations outside the        ranges specified herein for reasons such as poor health,        advanced age, compromised metabolism, renal failure, disease,        etc.

As used herein and unless otherwise specified, the drug or activeingredient included in the injectable composition can be present in freebase, salt, amorphous, crystalline, anhydrous, hydrate, optically pure,optically enriched or racemic forms thereof. Combinations of thesevarious forms are also within the scope of the invention. A prodrug,metabolite or derivative of the drug can also be included. In someembodiments, the drug is present in free base form.

In some embodiments, the aromatase inhibitor compound is in suspensionin a solution containing DMSO and PLA and the aromatase inhibitorrepresents between 20-30% by weight of the total composition.

In some embodiments, the aromatase inhibitor compound is in suspensionin a solution containing DMSO and PLA and aromatase inhibitor comprisesabout 25% by weight of the total composition.

According to another aspect, the aromatase inhibitor compound of generalformula (1) has the following particle size distribution:

-   -   <10% of the particles less than 20 microns,    -   <10% of the particles greater than 350 microns and    -   d0.5 between 70-200 microns.

In some embodiments, the aromatase inhibitor compound is letrozole oranastrozole, either alone or in combination. The ratio of letrozole toanastrozole in the composition can range from 100:0 to 0:100,respectively.

In some embodiments, the solution formed by DMSO and PLA comprises40-43% by weight of PLA (100% lactic) and 57-60% by weight of DMSO.

In a further preferred embodiment, the terminal group of the PLA is asan ester instead of a carboxylic acid. In other words, the PLA isend-capped to form an ester moiety.

In some embodiments, the active ingredient is subjected tosterilization, for example by gamma or beta radiation. Sterilization byradiation of the active ingredient may be carried out prior to itsinclusion in the implantable composition. The dose of radiation can beup to a maximum value of 35 kGy. Sterilization of the active ingredientcan also be carried out by terminal radiation of the product.

In another embodiment, the weight ratio of DMSO to drug is in the rangeof about 0.5 to about 3.7, about 1:1 to about 3:1, about 1.5:1 to about2:1 or about 1.7:1 to about 1.8:1.

In another embodiment, the viscosity of the solution containing DMSO andPLA is in the range of about 0.8 to about 1.8 Pa·s, about 0.8 to about1.5 Pa·s, about 0.8 to about 1.3 Pa·s or about 1 to 1.2 Pa·s.

Another aspect of the invention concerns use of the injectablecomposition herein as a medicine for the treatment of breast cancer,meaning a method of treating cancer by administration of the injectablecomposition. The invention provides a method of treating a disease,condition or disorder that is therapeutically responsive to aromataseinhibitor comprising administering an amount (or volume) of injectablecomposition comprising a therapeutically effective amount of thearomatase inhibitor. The composition can be administered every 30, 45,60 or 90 days.

In another embodiment, the maximum volume administered to a subject byintramuscular injection is about 2 mL and comprises a maximum of 500 mgof letrozole.

According to another aspect, the composition suitable for forming anintramuscular implant is characterized in that the AUC of the burst ofthe compound with the general formula (1) is not more than or is lessthan 10% of the total AUC and is not more than or is less than 50% ofthe total AUC over the first 30 days after injection.

A ready-to-use formulation can be prepared, for example, and included ina syringe ready for use for intramuscular injection. The sameformulation may form part, for example, of a kit of two syringes, onemale and one female or two male syringes linked by a connector in whichthe solution of polymer in DMSO is in one syringe and the aromataseinhibitor is in solid form in a second syringe.

Similarly, the final composition can be obtained by, for example,maintaining one syringe with the polymer and aromatase inhibitor insolid state and the solvent (DMSO) in a second syringe.

Reconstitution in these cases can be via direct joining of male andfemale syringes or by a connector where there are two male syringes, andpushing-pulling the plungers in both directions giving rise to thecombination of the products, and in this way to the solution of thepolymer and the suspension of the active ingredient.

Any alternative to this system that gives rise to the composition of thepresent invention is possible, so that any variation with other designsof the formulation, where the final combination results in the desiredproduct, for example maintaining the solvent or polymer solution in avial apart from the active ingredient, or for example keeping thepolymeric solution in a preloaded syringe and the aromatase inhibitor ina vial so that the polymeric solution is injected into the vial to giverise to the formation of the suspension, will be considered as possiblealternatives for the object of the present invention.

According to another aspect, the present invention provides a kitsuitable for the in situ preparation of the composition of the presentinvention, wherein the aromatase inhibitor compound of general formula(1) and the polymer are in a first container in solid form and the DMSOis in a second separate container.

According to another aspect, the present invention refers to a kitsuitable for the in situ preparation of the composition wherein thepolymer has been lyophilized.

According to another aspect, the present invention refers to a suitablekit for the in situ preparation of the composition wherein the aromataseinhibitor compound of general formula (1) is in a first container insolid form and the DMSO and the polymer are in a second container insolution.

According to another aspect, the present invention refers to a suitablekit for the in situ preparation of the composition wherein the aromataseinhibitor compound of general formula (1), the polymer and the DMSO arein a single container in the form of a suspension.

BRIEF DESCRIPTION OF THE FIGURES

The following figures are provided to help with the interpretation ofthe object of the present invention, but do not imply any limitation.

FIG. 1 depicts the plasma levels of letrozole (in ng/mL) obtained afterintramuscular administration to New Zealand white rabbits of theformulations described in example 1. The values shown correspond to themean plasma levels obtained in three animals of each group.

FIG. 2 depicts the plasma levels of letrozole (in ng/mL) obtained afterthe intramuscular administration to New Zealand white rabbits of theformulation described in example 2. The values shown correspond to themean plasma levels obtained in three animals of each group.

FIG. 3 depicts the plasma levels of letrozole (in ng/mL) obtained afterintramuscular administration to New Zealand white rabbits of theformulations described in example 3. The values shown correspond to themean plasma levels obtained in three animals of each group.

DETAILED DESCRIPTION OF THE INVENTION

The following terms are used interchangeably unless otherwise specified:“PLA”; “biodegradable thermoplastic polymer of polylactic acid”; “lacticpolyacid” and “polylactic acid”; “DMSO” and “dimethyl sulfoxide”.

As used herein, the term “polymeric solution” is taken to mean the fluidcomposition comprising a combination of the solvent and the polymerdissolved therein. In some embodiments, at least 80%, at least 90%, atleast 95%, at least 99% or all of the polymer is dissolved in thesolvent. If not otherwise specified, the viscosity value of thepolymeric solution or the injectable composition is given in Pa·s units.

Throughout the development of the present invention, the behavior ofvarious parameters that might have an influence on the result of theimplantable compositions for prolonged release in accordance with theinvention have been investigated. The parameters were the following.

1. Rheological Properties of the Polymeric Solutions and InherentViscosity

The behavior of the fluid, both of polymer solutions and the completeformulation, was evaluated by rheometry. In the case of matrices beingconsidered as a vehicle for letrozole, these all exhibited Newtonianbehavior. Viscosity is used herein as an indirect parameter, related tothe concentration of the polymer, for describing the behavior of theinjectable formulation with respect to its ability to control theinitial release of product

The PLA polymer exhibits an inherent or intrinsic viscosity in the rangeof about 0.16-0.60 dl/g, or about 0.20-0.50 dl/g as measured inchloroform at 25° C. at a concentration of 0.1% wt/v with a Ubbelhodesize 0c glass capillary viscometer or as measured in chloroform at 30°C. and at a concentration of 0.5% wt/v with a size 25 Cannon-Fenskeglass capillary viscometer. The PLA polymer is selected from free acid(not end-capped) or end-capped (e.g. alkyl esters such as lauryl ester,methyl ester, etc., referred to herein as PLA-e) terminal carboxylicpoly-lactide with polymer. The PLA polymer can be a poly(L-lactic acid)polymer, poly(D,L-lactic acid) polymer, poly (D-lactic acid) or acopolymer of those polymers. Polymers that are end-capped with esters(as opposed to the free carboxylic acid) demonstrate longer degradationhalf-lives. Suitable grades of PLA are commercially available from Uhdelnventa-Fischer (Berlin, DE), NatureWorks LLC (Blair, Neb., USA),Plastic Ingenuity (Cross Plains, Wis., USA), Toyobo, Dai Nippon PrintingCo., Mitsui Chemicals, Shimadzu, NEC, Toyota (Japan), PURACBiomaterials, Hycail (The Netherlands), Galactic (Belgium), Cereplast(U.S.A.), FkuR, Biomer, Stanelco, lnventa-Fischer (Germany),Snamprogetti (China), Boehringer Ingelheim (RESOMER® grades; IngelheimAm Rhein, DE), Evonik Industries (RESOMER® grades; Essen, DE), ALKERMES(Dublin, Ireland) or SIGMA ALDRICH (ST. Louis, Mo.). In someembodiments, the PLA is end-capped with an alkyl alcohol to form anester end group moiety. The uncapped PLA typically provides a fasterinitial release of drug in the first 30 days of a dosing period thandoes the PLA-e (see example below).

It was determined that the polymer solution should have a minimumviscosity of about 0.8 Pa·s, although this may preferably be around 1Pa·s, but not greater than about 1.8 Pa·s. The viscosity of the polymersolution can range from about 0.7 to about 2 Pa·s, about 0.8 to about1.8 Pa·s or about 1 to about 1.8 Pa·s. Polymer solutions, in DMSO andmeasured at 25° C., which are obtained within this viscosity range,provide the appropriate balance between solubilization of the activeingredient and its retention in the polymeric matrix, thereby providingclinically relevant plasma concentrations of letrozole or anastrozole,avoiding or minimizing release of excessive amounts of the activeingredient that may compromise the useful life of the implant during thediffusion phase of the active ingredient. When the active ingredient isadded, the viscosity increases, but the viscosity preferably does notexceed 4 or 3 Pa·s.

The following tables show the apparent viscosity of the most suitablepolymers in vitro and in vivo at different concentrations in DMSO at 25°C., as well as the viscosity of a final preferred formulation.

Viscosity of the PLA polymer Resomer ® R 203 S, irradiated as rawmaterial by beta radiation at a dose of 10 kGy, D,L-lactic polymer (% byw) Viscosity (Pa · s) 40% 41.5% 43% 45% mean 0.874 1.020 1.295 1.645 SD0.043 0.021 0.038 0.016

Viscosity of a preferred formulation Viscosity (Pa · s) Replicated meanSD 2.462 2.536 2.514 0.045 2.543

2. Particle Size of the Active Ingredient

The particle size of the active ingredient has an effect upon the finalbehavior of the formulation as it directly affects the process ofrelease from the formulation once it has been administered. Theimportance of this fundamental fact has not been previously described indocuments describing the preparation of prolonged release formulationscontaining aromatase inhibitors.

The use of different size fractions was evaluated in order to determineor narrow an interval that is suitable and as well defined as possible.Better than a specific and totally narrow size, it is more useful tohave a distribution of various crystal sizes enabling, to a certainextent, modulation of release in a staggered way. In this way, thesmallest sizes (below 50 microns) are not preferred because they veryeasily diffuse with the solvent during the formation of the implant.Particles of intermediate sizes, with mean values close to 100-300microns, are useful because they are retained by the matrix, requiremore time to dissolve and remain trapped in the implant during itssolidification. Particles above 300 microns require a high degree ofdegradation of the polymer, resulting in new latency periods in the lifecycle of the implant and excessive releases at the time of hydrolysis ofthe polymer, so the use of a high percentage or particles in this sizerange is not preferred.

It has been determined that elimination or reduction in the amount notonly of the smallest sizes but also of the intermediate to low sizes(50-100 microns) provides improvement to the product, given that, on theone hand, the final viscosity of the reconstituted product is reducedand, on the other hand, the pronounced burst effect is substantiallyprevented. Based upon the above, the active ingredient can possess aparticle size distribution characterized as follows: not more than 10%of the total volume of drug particles are less than 20 microns in size(equivalent diameter in volume as a function of applying Fraunhofertheory to irregularly shape particles; as measured by laser lightscattering, such as with a Malvern Mastersizer 2000) and not more than10% of the total volume of drug particles are greater than 350 micronsin size. In addition, the drug particles can possess a d0.5 valuepreferably in the range of about 70-200 microns.

In some embodiments, the drug exhibits one of the following particlesize distributions:

Parameter I II III IV V VI VII VIII VIII d0.1 (microns) 38 40 29 31 ≥20<70 ≥20 ≥20 ≥20 d0.5 (microns) 141 152 103 125 70-200 70-200 70-20070-125 125-200 d0.9 (microns) 312 320 245 304 ≤350 ≤350 >200 ≤350 ≤350

If not otherwise specified, the particle size distribution wasdetermined by light scattering technique using laser light diffractionin wet mode. It is known that particle size distribution results can bealtered as a function of the material treatment such the use of highconcentrate surfactant agents and/or strong force energies (vortex,sonication, etc). If nothing else is mentioned, drug is not treated andsamples are prepared by direct addition to the tank under moderatestirring (2000-3500 rpm). The methodology applied on present inventionto determine the drug particle size distribution mimics in a morefaithfully way the behavior of the drug powder on the injectableformulation herein described than other methods which apply forceenergies to the sample and/or use high concentrate surfactant agents forpreparing the samples in order to achieve high degrees of powderdisaggregation that cannot be simulated during the manual reconstitutionprocess of the formulation.

3. Degree of Suspension of the Active Ingredient in the SolutionContaining the PLA and the DMSO.

The presence of the active ingredient in solution or in suspensionaffects the process of release of the active ingredient once theformulation is injected intramuscularly. When drug is completelydissolved in the solution containing the polymer and DMSO, theintramuscular injection of the formulation gives rise to the release ofan excessive amount over the first few days due to the diffusion ofletrozole together with water-miscible solvent during the hardeningprocess of the polymeric carrier, followed by a latency period in whichin vivo release of the active ingredient is minimal and the finalrelease of drug occurs at the time when the polymer experiencesdegradation by hydrolysis. We describe herein how only formulationscontaining drug in suspension are capable of controlling the initialrelease of the active ingredient and of preventing these periods oflatency in which the formulation is not clinically effective.

In some embodiments, the drug is partially dissolved or completelyundissolved in the polymeric solution. In some embodiments, ≤5%, ≤10%,≤20% wt of the drug is dissolved in the solvent or polymeric solution toform the injectable composition. In some embodiments, >0%, ≥0.5%, ≥1%,≥5%, or ≥10% wt. of the drug is dissolved in the solvent or polymericsolution to form the injectable composition.

4. Weight Ratios and Content of Components

In some embodiments, the injectable composition comprises DMSO, drug andPLA. The composition can include one or more additional components thatdo not negatively impact the performance of the composition afteradministration to a subject. If present, such other component(s) can bepresent in a total amount of ≤20% wt, ≤15% wt., ≤10% wt, ≤5% wt, ≤1% wt.or ≤0.1% wt based upon the total weight of the composition. In someembodiments, the injectable composition consists essentially of orconsists of DMSO, drug and PLA.

A characteristic of the present composition is that the aromataseinhibitor compound of general formula (1) is suspended, and preferablypresent in an amount close to 25% by weight of the total composition, ina solution containing DMSO and PLA, which in some embodiments make upthe remaining 75% by weight of the total composition. As detailed inExample 1 if, for example, when the aromatase inhibitor compound iscompletely in solution, the in vivo response is unsatisfactory.

In some embodiments, the weight or mass ratio of DMSO to drug is in therange of about 0.5 to about 3.7, about 1:1 to about 3:1, about 1.5:1 toabout 2:1 or about 1.7:1 to about 1.8:1.

In some embodiments, the weight or mass ratio of DMSO to PLA is about1:1 to about 2.3:1, about 1.2:1 to about 1.8:1, about 1.3:1 to about1.5:1, or about 1.4:1.

In some embodiments, the weight or mass ratio of polymer solution todrug is about 1:1 to about 5.7:1, about, 2.3:1 to 4:1, about 2.8:1 toabout 3.2:1, or about 3:1.

In some embodiments, the weight or mass ratio of PLA to drug is about0.6:1 to about 2.8:1, about 1.0 to 2.0, about 1.1:1 to 1.6:1, or about1.2:1.

4. Method of Treatment

The invention provides a method of treating a disease, disorder orcondition that is therapeutically responsive to aromatase inhibitor.Exemplary diseases, disorders or conditions include, for example: a)adjuvant treatment (treatment following surgery with or withoutradiation) of postmenopausal women with hormone receptor-positive earlybreast cancer; b) metastasis in both pre and post-menopausal women; c)precocious puberty or children with pubertal gynecomastia; d) reducingestrogens, including estradiol, in men; e) hormonally-responsive breastcancer after surgery; f) ovarian stimulation; g) promote spermatogenesisin male patients suffering from nonobstructive azoospermia; h)endometriosis; i) cancer that is estrogen hormone receptor-positive orsensitive (non-small cell lung cancer, uterine leiomyomas, etc.); j)infertility in women with polycystic ovarian syndrome; k) ovariancancer; l) breast cancer that is estrogen hormone receptor positive orsensitive; j) priming for in vitro maturation cycles; k) preoperativetreatment with letrozole in premenopausal women undergoing laparoscopicmyomectomy of large uterine myomas; I) short stature in peripubertalboys; m) unexplained infertility or infertility with unknown oruncertain etiology; n) idiopathic central precocious puberty in boys.

The method comprises administering an amount (or volume) of injectablecomposition comprising a therapeutically effective amount of thearomatase inhibitor. The composition can be administered every 30, 45,60, 90, 120 or 150 days, or every month, every two months, every threemonths, every four months, every five months, every six months, or asoften as needed for as many times needed to ameliorate the disease,disorder or condition. Combinations of the dosing regimens herein arecontemplated. The composition provides therapeutic plasma levels for aperiod of at least 1, at least 2, at least 3, at least 4, at least 5 orat least 6 months following administration of a dose of aromataseinhibitor.

A dose of letrozole administered at the beginning of a dosing periodwill typically range from about 50 to about 750 mg, and the dose istypically included in an approximate volume of injectable compositionranging from about 0.1 to about 3 ml.

A dose of anastrozole administered at the beginning of a dosing periodwill typically range from about 30 to about 200 mg, and the dose istypically included in a volume of injectable composition ranging fromabout 0.1 to about 1.5 ml.

The intramuscular dose can be administered to any muscle or muscle grouptypically recognized by the pharmaceutical industry as a suitable sitefor an injectable composition. In some embodiments, the composition isadministered to the gluteal and/or deltoid muscles. The composition canalso be administered to the quadriceps muscle group.

Administration of a single dose is typically considered that amount ofinjectable composition administered to a subject within a period of upto 24 hours, up to 12 hours, up to 6 hours, up to 3 hours, up to onehour, up to 30 min, up to 15 min or up to 5 min.

A dose of injectable composition refers to an amount of injectablecomposition comprising a specified dose of drug. For example, a dose of25-200 mg of injectable composition comprises a dose of 25-200 mg ofdrug; therefore, the actual amount of injectable compositionadministered would be greater than 25-200 mg, the actual amount ofinjectable composition being determined according to the content drug inthe injectable composition. The composition can also be used toadminister drug according to other dosing regimens accepted by theregulatory and clinical communities. The dose can be administered on amg of drug per kg of body weight basis.

A dose can be administered to a single muscular site or can be dividedinto two or more portions and administered to two or more muscular sitesof a subject. For example, a first portion of a dose can be administeredto a first section of gluteal muscle and a second portion of the dosecan be administered to a second section of gluteal muscle of a subject.

As used herein, the term “dosing period” refers to the period of days orweeks as measured from the initial day after administration of a dose toat least 30 days, at least 45 days, at least 60 days, at least 90 days,at least 120 days, etc. after administration or to administration of asubsequent dose. During the dosing period, the implant will providetherapeutic plasma levels of drug for at least at least 1 month, atleast two months, at least three months, at least four months, at least5 months, or at least 6 months. A dosing period can end after expirationof a predetermined number of days or after the plasma level of drugdrops below therapeutic levels.

As used herein, a “treatment period” refers to the weeks, months oryears during which implants of the invention are administered to asubject. A treatment period generally comprises plural dosing periods.Dosing periods can occur sequentially or in an overlapping manner duringa treatment period. For example, a first dose of injectable compositionis administered and a second dose of injectable composition can beadministered at a time following administration of the first dose, suchthat each dose will have its own corresponding dosing period, and thedosing periods would overlap. Dosing periods will typically besequential or overlap by no more than one to seven days.

The injectable composition can be administered to a subject in one ormore injection sites on the same day and still be considered as beingpart of the same dosing period. For example, part of a dose can beadministered to a first injection site and another part of the same dosecan be administered to another injection site. A single-body implantwill form at each injection site. Such a mode of administration within asame day is considered to be administration of a single dose with asingle dosing period.

Alternatively, administration can be modified such that there is onepoint of needle entry into the subject but more than one injection sitebelow the skin, which can be achieved by making a first penetration intothe skin and muscle and administering a portion of a dose, thenpartially withdrawing and redirecting the needle into another section ofmuscle, while maintaining the tip of the needle beneath the skin, andthen injecting another portion of the dose into this other section ofmuscle. Such a mode of administration is still considered to beadministration of a single dose within a single dosing period.

In another embodiment, the injectable depot composition is sterile as afinished product. In another embodiment, the biocompatible polymer issterilized previously to its aseptic filling process, preferably byirradiation or by other process, e.g. filtration.

The plasma concentration profile during the dosing period can exhibitone, two, or more maxima and one, two or more minima. An initial maximumcan be caused by dissolution of drug during the initial day(s) of thedosing period followed by a slowing of the release thereof and anothermaximum can be caused by increased rate of release during the remainingdays of the dosing period. Embodiments of the invention include thosewherein: a) the plasma profile exhibits a maximum during the first thirdof the dosing period; b) the plasma profile exhibits a maximum duringthe second third of the dosing period; c) the plasma profile exhibits amaximum during the final third of the dosing period; and/or d) theplasma profile is substantially level (a standard deviation within ±30%,±25%, ±20%, ±15%, ±10% or ±5% of the average or mean) during the dosingperiod.

The injectable depot composition provides an adequate plasma levelprofile for drug after administration during a dosing period. An“adequate plasma level profile” is considered as providing a burst ofdrug that is is not more than or is less than 10% of the total AUC andis not more than or is less than 50% of the total AUC over the first 30days after injection. In some embodiments, the area under the curve(AUC) of the burst is less than 10% compared to the total AUC, andideally less than 5%, during a dosing period.

In some embodiments, the injectable depot composition provides a plasmalevel profile for drug as follows.

Percentage of Drug total AUC During the Period Following Administration(day) From day 30 up to day 60 or end of Day-0 up to day 3 From day 3 today 30 dosing period NMT 10% of total AUC NMT 50% of total AUC ≥50% oftotal AUC NMT 5% of total AUC NMT 50% of total AUC ≥50% of total AUC

The implant of the invention can provide substantially improved plasmalevels of drug when compared to another injectable formulation (notaccording to the invention) containing the same drug when administeredon an equivalent dose basis.

All values disclosed herein may have standard technical measure error(standard deviation) of ±10%. The term “about” is intended to mean ±10%,±5%, ±2.5% or ±1% relative to a specified value, i.e. “about” 20% means20±2%, 20±1%, 20±0.5% or 20±0.25%.

EXAMPLES

The following examples are illustrative of the invention and are not tobe considered limiting.

Example 1 Study of the Influence of the Physical Form of the ActiveIngredient in the Formulation: Suspension vs. Solution

The influence of the physical form of letrozole in the injectablesolution (solution vs. suspension of the active ingredient) wasevaluated by the use of the formulation described below:

Formulation 1: formulation with letrozole in solution Ingredient Amount(mg, % wt) Syringe 2.25 ml male Lactic acid polymer (ester terminalgroup) of 55.20 (35.8%) intrinsic viscosity of 0.3 dl/g, irradiated asraw material at 10 kGy. Dimethyl sulfoxide 82.80 (53.7%) Syringe 2.25 mlfemale Letrozole 16.20 (10.5%)

-   -   Weight ratio of DMSO to PLA is about 1.5:1. Weight ratio of        polymer solution to letrozole is about 8.5:1. Weight ratio of        PLA to letrozole is about 3.4:1. Weight ratio of DMSO to        letrozole is about 5.1:1.

Formulation 2: formulation with letrozole in suspension IngredientAmount (mg) Syringe 2.25 Lactic acid polymer (ester terminal group)38.80 (30%) ml male of intrinsic viscosity of 0.3 dl/g, irradiated asraw material at 10 kGy. Dimethyl sulfoxide 58.30 (45%) Syringe 2.25Letrozole 32.40 (25%) ml female

-   -   Weight ratio of DMSO to PLA is about 1.5:1. Weight ratio of        polymer solution to letrozole is about 3:1. Weight ratio of PLA        to letrozole is about 1.2:1. Weight ratio of DMSO to letrozole        is about 1.8:1.

Letrozole particle size in formulation 2 was characterized by thetechnique of laser ray diffraction (Malvern Mastersizer 2000, suspendedin water until obscuration of 9.41%) and had the following distribution(in % volume): d(0.1)=38.21 μm, d(0.5)=141.35 μm and d(0.9)=312.13 μm.

In both cases, reconstitution of the product was carried out byconnection of the male and female syringes and successive movements ofthe plungers in both directions until complete solution of the polymerhad been achieved.

Study of In Vivo Release in New Zealand White Rabbits

Trials of in vivo release for the present document were carried out bydetermination of pharmacokinetic profiles of letrozole and anastrozolein plasma after intramuscular administration in experimental animalmodels, rabbits and/or dogs.

For quantification of letrozole in dog and rabbit plasma a techniquebased on high performance liquid chromatography with fluorescencedetector HPLC-FLD with mass-mass detector using a liquid-liquidextraction with ethylene acetate as the organic solvent and resuspensionfor analysis in reverse phase with isocratic elution. Carvedilol wasused as the internal standard and the process time was 8.5 min with aletrozole retention time of 7.8 min and applying wavelengths of 240 nm(λ excitation) and 315 nm (λ emission). The validated concentrationinterval was from 5 (LLOQ) to 500 ng/mL, that is with a lower limit ofquantification or minimum quantifiable analyte concentration of theanalytical technique of 5 ng/mL and a maximum validated concentration of500 ng/mL. Calibration curves obtained were characterized with acorrelation coefficient of over 0.99. Precision and intra-assay andinter-assay accuracy was less than 20% for the LLOQ and less than 15%for the other QCs, that is, of the other known concentration samplesused as quality controls in conducting the analysis. The bioanalyticalmethod was validated over three days and the results met the acceptancecriteria described in the FDA guide: “Bioanalytical Method Validation”.

Samples of letrozole in dog and rabbit plasma were demonstrated to bestable at room temperature for up to 6 hours. Processed samples could bestored in the sampler at 4° C. for 24 hours without noticing any changein the precision and accuracy of the analysis. Cycles offreezing/thawing carried out did not affect the stability of letrozolein dog and rabbit plasma. Long term stability of the samples stored at−80° C. demonstrated stability for 132 days.

Formulations 1 and 2 were administered intramuscularly in the gluteusmuscle of New Zealand white rabbits with approximate body weight of 3kg. Three animals were used for each group and they were injected withan amount of formulation corresponding to 5.4 mg/kg for formulation 1and 10.8 mg/kg for formulation 2. After injection, samples of plasmawere collected from the rabbits at previously established sampling timesof up to 231 days after the injection. The results obtained are shown inFIG. 1. FIG. 1 shows that administration of the double dose offormulation 2 compared to formulation 1 in New Zealand white rabbitsgave rise to similar initial plasma levels. Given that the dose used informulation 1 was half that used in formulation 2, the clear importanceof controlling the physical form of the active ingredient in theformulation could be seen. Letrozole, being in solution in formulation1, diffuses with the solvent to a greater extent than in the case ofletrozole in formulation 2. It can also be seen that in the case offormulation 1 the plasma levels fell swiftly, and did not start torecover until day 154 after injection, the time at which additionalactive ingredient is released due to the hydrolytic degradation of thepolymer that retains it. Formulation 2 was able to maintain continuoussignificantly high levels of letrozole in rabbit plasma for more than 4months.

Example 2 Study of the Influence of the Terminal Group of the Polymer

Evaluation of the influence of the terminal carboxylic or ester(N-capped) group of the polymer was evaluated by the use of theformulations described below:

Formulation 1: formulation of lactic acid polymer terminating in acarboxylic group Ingredient Amount (mg) Syringe 2.25 Lactic acid polymer(carboxylic terminal 38.80 ml male group) of intrinsic viscosity of 0.3dl/g, irradiated as raw material at 10 kGy. Dimethyl sulfoxide 58.30Syringe 2.25 Letrozole 32.40 ml female

-   -   Weight ratio of DMSO to PLA is about 1.5:1. Weight ratio of        polymer solution to letrozole is about 3:1. Weight ratio of PLA        to letrozole is about 1.2:1. Weight ratio of DMSO to letrozole        is about 1.8:1.

Formulation 2: formulation with lactic acid polymer terminating in anester group Ingredient Amount (mg) Syringe 2.25 Lactic acid polymer(ester terminal group) 38.80 ml male of intrinsic viscosity of 0.3 dl/g,irradiated as raw material at 10 kGy. Dimethyl sulfoxide 58.30 Syringe2.25 Letrozole 32.40 ml female

-   -   Weight ratio of DMSO to PLA is about 1.5:1. Weight ratio of        polymer solution to letrozole is about 3:1. Weight ratio of PLA        to letrozole is about 1.2:1. Weight ratio of DMSO to letrozole        is about 1.8:1.

Letrozole particle size in formulations 1 and 2 were characterized bythe technique of laser ray diffraction (Malvern Mastersizer 2000,suspended in water until obscuration of 9.41%) and had the followingdistribution (in % volume): d(0.1)=38.21 μm, d(0.5)=141.35 μm andd(0.9)=312.13 μm.

In both cases, reconstitution of the product was carried out byconnection of the male and female syringes and successive movements ofthe plungers in both directions until complete solution of the polymerhad been achieved.

In parallel, the viscosity of the solution containing the components ofthe male syringe was evaluated, in amounts proportionally equivalent tothose described (41.5% by weight of polymer with respect to the weightof solution) at 25° C. by the use of a rotational viscometer (Haake).The viscosity result values obtained are shown in the following table:

Polymer (beta irradiated at 10 kGy as raw material) Viscosity at 25° C.(Pa · s) PLA-carboxylic terminal group 1.221 PLA-ester terminal group1.054

Study of In Vivo Release in New Zealand White Rabbits

In the present example, formulations 1 and 2 were administeredintramuscularly in the gluteus muscle of New Zealand white rabbits withapproximate body weight of 3 kg. Three animals were used for each groupand they were injected with an amount of formulation corresponding to10.8 mg/kg for both formulations. After injection, samples of plasmawere collected from the rabbits at previously established sampling timesof up to 175 days after injection. The results obtained are shown inFIG. 2.

FIG. 2 shows that administration of formulation 1 gave rise to very highinitial letrozole plasma levels after injection. However, the levelsprogressively reduced until the levels were undetectable at 119 days.Formulation 2, on the other hand, resulted in significantly high levelsover a clearly longer period of time. The high hydrophilicity of thepolymer with the carboxylic terminal group and its higher wettabilitycompared to the polymer with ester termination is probably behind thehigher release of the active ingredient over the early phases of thestudy. Formulation 2, however, was able to modulate release of letrozoleto a higher degree than formulation 1, giving rise to levels that weremore sustainable over time. The % area under the curve of letrozoleplasma levels in each formulation over the total area under the curveare shown in the following table.

% AUC first % AUC up AUC total Formulation 3 days to day 30 (ng h/ml) 13.981 66.630 328086.1 2 2.806 36.651 352267.6

Accordingly, in some embodiments, the PLA in the composition is anend-capped PLA (PLA-e).

Example 3 Study of the Influence of the Terminal Group of the Polymer inBeagle Dogs

Evaluation of the influence of the terminal carboxylic or ester(N-capped) group of the polymer was evaluated by the use of theformulations described below:

Formulation 1: formulation of lactic acid polymer terminating in acarboxylic group Ingredient Amount (mg, % wt) Syringe 2.25 ml maleLactic acid polymer (carboxylic terminal group) 107.6 (31.1%) ofintrinsic viscosity of 0.3 dl/g, irradiated as raw material at 10 kGy.Dimethyl sulfoxide 151.7 (43.9%) Syringe 2.25 ml female Letrozole 86.5(25%) 

-   -   Weight ratio of DMSO to PLA is about 1.4:1. Weight ratio of        polymer solution to letrozole is about 3:1. Weight ratio of PLA        to letrozole is about 1.24:1. Weight ratio of DMSO to letrozole        is about 1.75:1.

Formulation 2: formulation with lactic acid polymer terminating in anester group Amount Ingredient (mg) Syringe 2.25 Lactic acid polymer(ester terminal 107.6 ml male group) of intrinsic viscosity of 0.3 dl/g,irradiated as raw material at 10 kGy. Dimethyl sulfoxide 151.7 Syringe2.25 Letrozole 86.5 ml female

Letrozole particle sizes in formulations 1 and 2 were characterized bythe technique of laser ray diffraction (Malvern Mastersizer 2000,suspended in water until obscuration of 9.41%) and had the followingdistribution (in % volume): d(0.1)=38.21 μm, d(0.5)=141.35 μm andd(0.9)=312.13 μm.

In both cases, reconstitution of the product was carried out byconnection of the male and female syringes and successive movements ofthe plungers in both directions until complete solution of the polymerhad been achieved.

The apparent viscosity at 25° C. of fully reconstituted formulation 2gave a value of 2.865 Pa·s.

In parallel, the viscosity of the solution containing the components ofthe male syringe was evaluated, in amounts proportionally equivalent tothose described (41.5% by weight of polymer with respect to the weightof solution) at 25° C. by the use of a rotational viscometer (Haake).The viscosity result values obtained are shown in the following table:

Polymer (beta irradiated at 10 kGy as raw material) Viscosity at 25° C.(Pa · s) PLA-carboxylic terminal group 1.221 PLA-ester terminal group1.054

Study of In Vivo Release in Beagle Dogs

In the present example, formulations 1 and 2 were administeredintramuscularly in the gluteus muscle of Beagle dogs with approximatebody weight of 10 kg. Three animals were used for each group and theywere injected with an amount of formulation corresponding to 86.5 mg/kgfor both formulations. After injection, samples of plasma were collectedfrom the dogs at previously established sampling times of up to 472 daysafter injection. The results obtained are shown in FIG. 3.

FIG. 3 shows that the difference observed in the previous examplebetween the two polymers was significantly higher in dogs. The lowerbody temperature of the Beagle dog (some 2.4° C. lower than the NewZealand white rabbit) slowed down the diffusion process, probably due toa combination of effects between the lower speed of hydrolysis of thepolymers at the lower temperature and lower diffusion of the activeingredient across the matrix also due to the lower body temperature. Ahigher influence of polymer hydrophilicity in the kinetic profile ofletrozole was observed in this situation of reduced diffusion and speedof degradation. The observation of a continuous increase in letrozoleplasma levels over the first 14 to 21 days demonstrates an enterohepaticcirculation phenomenon that has been demonstrated by populationpharmacokinetic analysis of the data obtained (Nonmen). Thisenterohepatic circulation of letrozole is likely to be also observablein humans. The % area under the curve of letrozole plasma levels in eachformulation over the total area under the curve are shown in thefollowing table:

% AUC % AUC up AUC total Formulation first 3 days to day 30 (ng h/ml) 11.527 74.963 460177.6 2 0.537 36.940 482879.8

Example 4 Exploration of Compositional Range Limits

Formulations containing the ingredients and amounts specified below areprepared and evaluated according to any of Examples 1-3. Theformulations provide a plasma profile such that the burst of thecompound of general formula (1) (drug) is less than about 10% of thetotal AUC and not more than about 50% of the total AUC over the first 30days after injection.

Formulation 4a: formulation of lactic acid polymer terminating in acarboxylic group Ingredient Amount (% wt) Syringe 0.5-5 ml male Lacticacid polymer (PLA)   15-42.5 Dimethyl sulfoxide   25-59.5 (Same asabove) Syringe Letrozole or anastrozole 15-50 0.5-5 ml female

-   -   Weight ratio of DMSO to PLA is about 1.0:1 to 2.3:1. Weight        ratio of polymer solution to letrozole is about 1.0:1 to 5.7:1.        Weight ratio of PLA to drug is about 0.4:1 to 2.8:1. Weight        ratio of DMSO to drug is about 0.5:1 to 3.7:1.

Formulation 4b: formulation of lactic acid polymer terminating in acarboxylic group Ingredient Amount (% wt) Syringe 0.5-5 ml male Lacticacid polymer (PLA) 28-36 Dimethyl sulfoxide 38.5-52   (Same as above)Syringe Letrozole or anastrozole 20-30 0.5-5 ml female

-   -   Weight ratio of DMSO to PLA is about 1.2:1 to 1.9:1. Weight        ratio of polymer solution to drug is about 2.3:1 to 4.0:1.        Weight ratio of PLA to drug is about 1.0:1 to 1.8:1. Weight        ratio of DMSO to drug is about 1:1 to 3:1 or 1.5:1 to 2:1.

Formulation 4c: formulation of lactic acid polymer terminating in acarboxylic group Ingredient Amount (% wt) Syringe 0.5-5 ml male Lacticacid polymer (PLA) 29.6-32.7 Dimethyl sulfoxide 42.2-45.6 (Same asabove) Syringe Letrozole or anastrozole 24-26 0.5-5 ml female

-   -   Weight ratio of DMSO to PLA is about 1.3:1 to 1.5:1. Weight        ratio of polymer solution to drug is about 2.8:1 to 3.2:1.        Weight ratio of PLA to drug is about 1.1:1 to 1.4:1. Weight        ratio of DMSO to drug is about 1.7:1 to 1.8:1.

Formulation 4d: formulation of lactic acid polymer terminating in anester group Ingredient Amount (% wt) Syringe 0.5-5 ml male Lactic acidpolymer, 15-42.5 ester terminal group (PLA-e) Dimethyl sulfoxide 25-59.5(Same as above) Syringe Letrozole or anastrozole 15-50   0.5-5 ml female

-   -   Weight ratio of DMSO to PLA is about 1.0:1 to 2.3:1. Weight        ratio of polymer solution to drug is about 1.0:1 to 5.7:1.        Weight ratio of PLA to drug is about 0.4:1 to 2.8:1. Weight        ratio of DMSO to drug is about 0.5:1 to 3.7:1.

Formulation 4e: formulation of lactic acid polymer terminating in anester group Ingredient Amount (% wt) Syringe 0.5-5 ml male Lactic acidpolymer, 28-36 ester terminal group (PLA-e) Dimethyl sulfoxide 38.5-52  (Same as above) Syringe Letrozole or anastrozole 20-30 0.5-5 ml female

-   -   Weight ratio of DMSO to PLA is about 1.2:1 to 1.9:1. Weight        ratio of polymer solution to drug is about 2.3:1 to 4.0:1.        Weight ratio of PLA to drug is about 1.0:1 to 1.8:1. Weight        ratio of DMSO to drug is about 1:1 to 3:1 or 1.5:1 to 2:1.

Formulation 4f: formulation of lactic acid polymer terminating in anester group Ingredient Amount (% wt) Syringe 0.5-5 ml male Lactic acidpolymer, 29.6-32.7 ester terminal group (PLA-e) Dimethyl sulfoxide42.2-45.6 (Same as above) Syringe Letrozole or anastrozole 24-26 0.5-5ml female

-   -   Weight ratio ot UMSU to PLA is about 1.3:1 to 1.5:1. Weight        ratio ot polymer solution to drug is about 2.8:1 to 3.2:1.        Weight ratio of PLA to drug is about 1.1:1 to 1.4:1. Weight        ratio of DMSO to drug is about 1.7:1 to 1.8:1.

Example 5

Compositions containing the ingredients and amounts specified below areprepared and evaluated according to any of Examples 1-3. Thecompositions provide a plasma profile such that the burst of thecompound of general formula (1) (drug) is less than about 10% of thetotal AUC and not more than about 50% of the total AUC over the first 30days after injection. The compositions provide therapeutic plasma levelsof aromatase inhibitor for a period of at least 60 days afteradministration.

Polymer Polymer Polymer Inherent Component Solution lactic/glycolicViscosity Amount (mg) Viscosity Formulation Drug ratio (dL/g) SolventDrug Polymer Solvent (Pa · s) A Letrozole 100:0 0.30 DMSO 25 85.2 127.81.20 B Letrozole 100:0 0.30 DMSO 25 63.9 149.1 0.26

The implantable formulations were prepared by completely dissolving thepolymer in the solvent and subsequently adding the drug in saidpolymeric solution.

The injection of an amount of formulation equivalent to 5.4 mg letrozoleto New Zealand White rabbits resulted in controlled initial plasmalevels (first 3 days) with a duration period of at least 56 days whenpolymers having an inherent viscosity of 0.38-0.43 dL/g were used.

As used herein, the term about is taken to mean ±10%, ±5% or ±1% of aspecified value.

1-58. (canceled)
 59. A method of treating a disease, condition ordisorder that is therapeutically responsive to aromatase inhibitor ormetabolite thereof, the method comprising administering atherapeutically effective amount of said aromatase inhibitor in aninjectable composition consisting of about 25% wt of said aromataseinhibitor, which is letrozole having a particle size distributionselected from any of the following: <10% of the particles are less than20 microns, <10% of the particles are greater than 350 microns, and ad0.5 between 70-200 microns; or d0.1 of 38.21 microns, d0.5 of 141.35microns, and d0.9 of 312.13 microns; and the remaining balance of saidinjectable composition comprising polymeric solution comprising 57-60%wt of DMSO; and 40-43% wt of biodegradable poly(lactic acid) polymer(PLA), wherein the polymeric solution has a viscosity in the range of0.8-1.5 Pa·s. as measured at 25° C.
 60. The method of claim 59, whereinsaid amount is about 0.1 to 3 ml and comprises about 50 to 750 mg ofsaid aromatase inhibitor, said amount is about 0.1 to 1.5 ml andcomprises about 30 to 200 mg of said aromatase inhibitor, or said amountis about 2 ml and comprises about 500 mg of said aromatase inhibitor.61. (canceled)
 62. (canceled)
 63. The method of claim 59, wherein saidinjectable composition provides plasma levels of aromatase inhibitorsufficient to provide an in vivo suppression of serum estrogens of atleast about 50% for estradiol and at least about 70% for estrone in thesteady state during a dosing period.
 64. The method of claim 59, whereinsaid injectable composition is administered intramuscularly.
 65. Themethod of claim 64, wherein said injectable composition is administeredto the gluteal muscles, quadricep muscles, and/or deltoid muscles. 66.The method of claim 64, wherein a first portion of said injectablecomposition is administered to a first site and a second portion ofinjectable composition is administered to a second site.
 67. The methodof claim 64, wherein said injectable composition is administered to asingle muscle site or two or more muscle sites.
 68. The method of claim59, wherein, after administration a) the plasma profile exhibits amaximum during the first third of a dosing period; b) the plasma profileexhibits a maximum during the second third of a dosing period; c) theplasma profile exhibits a maximum during the final third of a dosingperiod; and/or d) the plasma profile is substantially level, within astandard deviation of ±30%, during a dosing period.
 69. The method ofclaim 59, wherein said injectable composition is administered inoverlapping or sequential dosing periods.
 70. The method of claim 59,wherein, after administration, said injectable composition provides aplasma level profile for aromatase inhibitor (AI) as follows: Percentageof AI total AUC During the Period Following Administration (day) Fromday 30 up to day 60 or end Day-0 up to day 3 From day 3 to day 30 ofdosing period NMT 10% of total AUC NMT 50% of total AUC ≥50% of totalAUC NMT 5% of total AUC NMT 50% of total AUC ≥50% of total AUC.


71. The method of claim 59, wherein the burst AUC, within 0-3 days afteradministration, is less than 10% of the total AUC calculated for the 60days after administration, is less than 5% of the total AUC calculatedfor the 60 days after administration, or wherein, followingadministration to a subject, the AUC of the burst of said aromataseinhibitor is less than about 10% of the total AUC after administrationand not more than about 50% of the total AUC over the first 30 daysafter administration.
 72. (canceled)
 73. The method of claim 59, whereinsaid injectable composition provides therapeutic plasma levels for aperiod of at least 2 months or at least 3 months followingadministration.
 74. (canceled)
 75. The method of claim 59, wherein saiddisease, disorder or condition is selected from the group consisting of:a) adjuvant treatment of postmenopausal women with hormonereceptor-positive early breast cancer; b) metastasis in both pre andpost-menopausal women; c) precocious puberty or children with pubertalgynecomastia; d) reducing estrogens, including estradiol, in men; e)hormonally-responsive breast cancer after surgery; f) ovarianstimulation; g) promote spermatogenesis in male patients suffering fromnonobstructive azoospermia; h) endometriosis; i) cancer that is estrogenhormone receptor-positive or sensitive; j) infertility in women withpolycystic ovarian syndrome; k) ovarian cancer; l) breast cancer that isestrogen hormone receptor positive or sensitive; j) priming for in vitromaturation cycles; k) preoperative treatment with letrozole inpremenopausal women undergoing laparoscopic myomectomy of large uterinemyomas; 1) short stature in peripubertal boys; m) unexplainedinfertility or infertility with unknown or uncertain etiology; n)idiopathic central precocious puberty in boys; o) treatment followingsurgery with or without radiation of postmenopausal women with hormonereceptor-positive early breast cancer; p) non-small-cell lung cancer; orq) uterine leiomyomas.
 76. (canceled)
 77. The method of claim 59,wherein said injectable composition is administered every 30 Days, every45 days, every 60 days, every 90 days, every 120 days, every 150 days,every month, every two months, every three months, every four months,every five months, every six months, or as often as needed to amelioratethe disease, disorder or condition.
 78. The method of claim 59, whereinsaid injectable composition provides therapeutic plasma levels of saidaromatase inhibitor or metabolite thereof for a period of at least 1months, at least 4 months, at least 5 months, or at least 6 monthsfollowing administration.
 79. The method of claim 59, wherein the PLAhas been irradiated with a maximum dose of 35 kGy.
 80. The method ofclaim 59, wherein the polymer has been lyophilized.
 81. The method ofclaim 59, wherein the PLA is end-capped with a carboxylic acid group orwith an ester group.
 82. (canceled)
 83. A method of treating a disease,condition or disorder that is therapeutically responsive to aromataseinhibitor or metabolite thereof, the method comprising administering atherapeutically effective amount of said aromatase inhibitor in aninjectable composition consisting of about 25% wt of said aromataseinhibitor, which is letrozole having a particle size distributionselected from any of the following: <10% of the particles are less than20 microns, <10% of the particles are greater than 350 microns, and ad0.5 between 70-200 microns; or d0.1 of 38.21 microns, d0.5 of 141.35microns, and d0.9 of 312.13 microns; and the remaining balance of saidinjectable composition comprising polymeric solution comprising 57-60%wt of DMSO; and 40-43% wt of biodegradable poly(lactic acid) polymer(PLA), wherein the polymeric solution has a viscosity in the range of0.8-1.5 Pa·s. as measured at 25° C.; and wherein, after administrationa) the plasma profile exhibits a maximum during the first third of adosing period; b) the plasma profile exhibits a maximum during thesecond third of a dosing period; c) the plasma profile exhibits amaximum during the final third of a dosing period; and/or d) the plasmaprofile is substantially level, within a standard deviation of ±30%,during a dosing period; and after administration said injectablecomposition provides therapeutic plasma levels for a period of at least2 months or at least 3 months.
 84. The method of claim 83, wherein,after administration, said injectable composition provides a plasmalevel profile for aromatase inhibitor (AI) as follows: Percentage of AItotal AUC During the Period Following Administration (day) From day 30up to day 60 or end Day-0 up to day 3 From day 3 to day 30 of dosingperiod NMT 10% of total AUC NMT 50% of total AUC ≥50% of total AUC NMT5% of total AUC NMT 50% of total AUC ≥50% of total AUC.


85. The method of claim 83, wherein the burst AUC, within 0-3 days afteradministration, is less than 10% of the total AUC calculated for the 60days after administration, is less than 5% of the total AUC calculatedfor the 60 days after administration, or wherein, followingadministration to a subject, the AUC of the burst of said aromataseinhibitor is less than about 10% of the total AUC after administrationand not more than about 50% of the total AUC over the first 30 daysafter administration.
 86. The method of claim 83, wherein the PLA hasbeen irradiated with a maximum dose of 35 kGy.
 87. The method of claim83, wherein the PLA is end-capped with a carboxylic acid group or withan ester group.